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Eriodictyol, a natural flavonoid mainly distributed in citrus fruits and peanut, has been well-documented with possession of excellent anti-inflammatory, antioxidant, and anticancer bioactivities. This work focus on the protective effects of eriodictyol on LPS-induced neuroinflammation, amyloidogenesis, cognitive impairment, and the potential mechanisms involved. Behavioral tests and histological examinations showed that eriodictyol significantly prevented the memory and neuronal damage triggered by LPS. Consistently, eriodictyol (100 mg/kg) reduced the formation of Aβ_1–42 by 28.37 ± 16.71 pg/mL compared to the LPS group. In addition, high dose eriodictyol (100 mg/kg) also equilibrated the cholinergic system via suppressing AChE activity (0.1996 ± 0.0831 U/mgprot) and elevating ChAT activity (41.81 ± 24.72 U/g) as well as ACh level (5.093 ± 3.531 μg/mgprot) compared to the LPS group. Western blot results …